DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting

Cell Rep. 2022 Aug 30;40(9):111278. doi: 10.1016/j.celrep.2022.111278.

Abstract

Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment.

Keywords: CP: Metabolism; CP: Neuroscience; GATOR1; SUDEP; TSC; amino acids; cell signaling; epilepsy; fasting; mTOR; metabolomics; seizures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids
  • Animals
  • Fasting*
  • GTPase-Activating Proteins* / metabolism
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Mice
  • Mice, Knockout
  • Seizures* / metabolism

Substances

  • Amino Acids
  • Depdc5 protein, mouse
  • GTPase-Activating Proteins
  • Mechanistic Target of Rapamycin Complex 1